The alveolar-capillary system of the lung serves as a barrier for certain constituents and as a pathway for the exchange of other constituents among blood, the pulmonary tissue and its component structural elements and the alveolar gas phase. We plan to continue and extend current studies on the characterization of the several barrier components (endothelium, interstitium, epithelium) by means of a combination of three approaches: structural (electron microscopy and morphometry), functional (barrier parameters by Kedem-Katchalsky formulations of irreversible processes), and cellular. The preparations studied include normally perfused lungs in vivo, isolated perfused lungs, and surviving or cultured lung cells. We have found that increased outward filtration of water and solutes is associated with an increased number of pinocytotic vesicles in both endothelium and epithelium. We wish to test our working hypothesis that increased vesiculation is a response to increased tissue pressure and to examine other structural, functional and metabolic implications of this phenomenon. We also wish to determine the effect of various injurious agents (ethchlorvynol, alloxan, oleic acid, cytochalasin B, colchicine) on structural, functional and cellular characteristics and particularly in the production of vesiculation and cellular edema. At the functional level, we are obtaining values for filtration and reflection coefficients of the endothelium and for permeability coefficients of both endothelium and epithelium. Permeability coefficients increase with oil:water distribution coefficients but do not show expected variation with size for small hydrophilic solutes. Mathematical modeling and isolated cell studies suggest that calculated values reflect distribution volumes as well as permeabilities. By appropriate combinations of the several approaches we seek to determine the pathways (whether cell junctions, cytoplasm or vesicles) taken by water and various solutes (hydrophilic, lipophilic, macromolecular) across the endothelium and epithelium.